Acetylcholine-like and trimethylglycine-like PTA (1,3,5-triaza-7-phosphaadamantane) derivatives for the development of innovative Ru- and Pt-based therapeutic agents.

The PTA N-alkyl derivatives (PTAC2H4OCOMe)X (1X: 1a, X = Br; 1b, X = I; 1c, X = PF6; 1d, X = BPh4), (PTACH2COOEt)X (2X: 2a, X = Br; 2b, X = Cl; 2c, X = PF6), and (PTACH2CH2COOEt)X (3X: 3a, X = Br; 3c, X = PF6), presenting all the functional groups of the natural cationic compounds acetylcholine or trimethylglycine combined with a P-donor site suitable for metal ion coordination, were prepared and characterized by NMR, ESI-MS, and elemental analysis. The X-ray crystal structures of 1d and 2c were determined. Ligands 1c, 2b, and 3c were coordinated to Pt(II) and Ru(II) to give the cationic complexes cis-[PtCl2(L)2]X2 and [RuCpCl(PPh3)(L)]X (L = 1, 2, 3, X = Cl or PF6) designed with a structure targeted for anticancer activity. The X-ray crystal structure of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]PF6 (1cRu) was determined. The antiproliferative activity of the ligands and the complexes was evaluated on three human cancer cell lines.

Water-soluble Cp ruthenium complex containing 1,3,5-triaza-7-phosphaadamantane and 8-thiotheophylline derivatives: synthesis, characterization, and antiproliferative activity.

The new water-soluble ruthenium(II) mononuclear complexes [RuCp(X)(PTA)(L)] (X = 8-thio-theophyllinate (TTH(-)), L = PTA (1), L = PPh(3) (7)); (X = 8-methylthio-theophyllinate (8-MTT(-)), L = PTA (2), L = PPh(3) (8)), (X = 8-benzylthio-theophyllinate (8-BzTT(-)), L = PTA (3), L = PPh(3) (9)) and binuclear complexes [{RuCp(PTA)(L)}(2)-µ-(Y-κN7,N'7)] (Y = bis(S-8-thiotheophyllinate)methane (MBTT(2-)), L = PTA (4), L = PPh(3) (10)), (Y = 1,2-bis(S-8-thiotheophyllinate)ethane (EBTT(2-)), L = PTA (5), L = PPh(3) (11)), (Y = 1,3-bis(S-8-thiotheophyllinate)propane (PBTT(2-)); L = PTA (6), L = PPh(3) (12)) have been synthesized and characterized by NMR, IR spectroscopy and elemental analysis. The single crystal X-ray structure of [RuCp(8-MTT-κS)(PTA)(2)] (2) was also obtained. The antiproliferative activity of the complexes on cisplatin-sensitive T2 and cisplatin-resistant SKOV3 cell lines has been evaluated.

A new amido-phosphine of dichloroacetic acid as an active ligand for metals of pharmaceutical interest. Synthesis, characterization and tests of antiproliferative and pro-apoptotic activity.

We herein describe the synthesis and characterization of the new amido-phosphinic ligand 3,7­bis(dichloroacetyl)­1,3,7­triaza­5­phosphabicyclo[3.3.1]nonane (DCP), a derivative of dichloroacetic acid (DCA), whose ability to reverse the suppressed mitochondrial apoptosis in cancer cells is known. DCP was obtained by a double N-acylation of PTA (1,3,5­triaza­7­phosphaadamantane) occurring with loss of CH2, in appropriate conditions. Due to the hindered rotation around the amidic CN bonds, three rotameric forms of DCP were observed, whose ratio in solution was dependent on the solvent, while the X-ray crystal structure of DCP showed an opposite orientation of the two amidic carbonyl groups (anti rotamer). The lipophilic, air and thermally stable DCP was found able to act regiospecifically as a P-donor ligand toward soft metal ions. By ligand substitution on appropriate precursors, we obtained the complexes 1-9, where proapoptotic DCA is associated with metal ions of known cytotoxic activity on cancer cells (Pt2+, Pd2+, Ru2+, Re+, Au+). The antiproliferative activity of DCP and its complexes was tested in vitro, in comparison with cisplatin, on three human tumor cell lines: A2780 (ovarian cisplatin-sensitive), A2780cis (ovarian cisplatin-resistant) and K562 (erythroleukemic). The results showed that the simultaneous presence of DCP (containing two residues of proapoptotic DCA) and Pt(II) produces the best performances with respect to non-platinum complexes. Experiments of pro-apoptotic activity indicated that the antiproliferative activity of the most active DCP-Pt(II) complexes is associated with induction of apoptosis.

Solid lipid nanoparticles for the delivery of 1,3,5-triaza-7-phosphaadamantane (PTA) platinum (II) carboxylates.

The use of solid lipid nanoparticles (SLN) is a promising route for the delivery of platinum complexes aimed to anticancer activity. This paper describes the production and characterization of SLN suitable for the loading of Pt complexes containing the biocompatible phosphine 1,3,5-triaza-7-phosphaadamantane (PTA) as neutral ligand. After a screening of several lipidic phases, stearic acid-based SLN were identified as the most appropriate for the purpose. They were produced by emulsion-dilution method and then characterized in terms of dimension, polydispersity, time stability, pH balance and morphological aspect. Stearic acid SLN are designed as a system able to coordinate to platinum, acting as anionic carboxylic ligands, replacing the base carbonate of the Pt synthon [PtCO3(DMSO)2], where also DMSO can subsequently be substituted by phosphinic ligands, namely PTA. SLN functionalised with Pt-PTA were produced and characterized by this synthetic route. The toxicity of plain SLN and the antiproliferative effect of SLN functionalised with Pt-PTA were evaluated on two human cancer cell lines K562 and A2780. The results indicate that SLN can be exploited as a delivery system for Pt complexes with potential anticancer activity.

Bis(dimethylsulfoxide)carbonateplatinum(ii), a new synthon for a low-impact, versatile synthetic route to anticancer Pt carboxylates.

The work describes a new low-impact synthetic route to Pt(ii)-carboxylate complexes, a class of compounds provided with established anticancer activity. The process is based on the ligand substitution on [PtCO3(Me2SO-S)2] (), a new synthon that can be easily prepared in water with high yield, is stable as a solid, and is reactive in solution where all its ligands can be easily replaced. It reacts with acidic O-donors releasing CO2 as the only side-product, whose development also supplies a driving force toward the products. The substitution of carbonate led to new Pt-DMSO carboxylate complexes , while the total substitution of the ligands of complex gave new Pt-phosphino carboxylates in high yields. The X-ray crystal structures of complexes [Pt(d(-)-quinate-O,O')(Me2SO-S)2] (), [Pt(salicylate)(Me2SO-S)2] () and [Pt(salicylate)(PPh3)2] () were determined. The tests of the antiproliferative activity of complexes on two human tumoral cell lines, A2780 (cisplatin-sensitive) and SKOV-3 (cisplatin-resistant), showed that the PTA (PTA = 1,3,5-triaza-7-phosphaadamantane) complexes were the most active on both cell lines.

Lipid-based nanoparticles containing cationic derivatives of PTA (1,3,5-triaza-7-phosphaadamantane) as innovative vehicle for Pt complexes: Production, characterization and in vitro studies.

The aliphatic phosphine PTA (1,3,5-triaza-7-phosphaadamantane) is a promising ligand for metal complexes designed and developed as innovative inorganic drugs. In the present paper, an N-alkylated derivative of PTA, (PTAC16H33)X (X=I, C1, or X=PF6, C2) and its platinum coordination complex cis-[PtCl2(PTAC16H33)2](PF6)2, C3, were considered as components of cationic lipid nanoparticles (CLNs). Particularly, CLN1, CLN2 and CLN3 were obtained by adding derivatives C1, C2 or C3 during nanoparticles preparation, while CLN2-Pt were obtained by treating preformed CLN2 with Pt(II). It was demonstrated that CLN1, CLN2 and CLN3 can be produced with technological conventional methods. However, among the two here proposed protocols, the one based on the treatment of preformed nanoparticles appears more advantageous as compared to the other since it allows a quantitative association yield of Pt. As determined by ICP-OES, a content of P and Pt 2.2-fold and 2.5-fold higher in CLN2-Pt than in CLN3 was evidenced. For the first time was demonstrated that properly functionalized preformed nanoparticles can be efficiently used to obtain a post production Pt(II) complex while maintaining a cytotoxic activity toward cultured cells. In fact, the antiproliferative activity shown by CLN3, CLN2-Pt on the three model cancer cell lines was substantially similar and comparable to that of complex C3 in dmso solution. Thus N-alkylated-PTA derivatives in CLNs could be proposed as innovative biocompatible and water dispersible nanoparticles carrying lipophilic Pt complexes becoming an interesting and improved system with respect to dmso solution.

Long-chain cationic derivatives of PTA (1,3,5-triaza-7-phosphaadamantane) as new components of potential non-viral vectors.

The purpose of this study was to investigate the potential of new positively charged solid lipid nanoparticles (SLN) to convey nucleic acids. The cationic character of SLN was obtained by adding as cationic molecules two different long-chain cationic phosphines (CP), namely hexadecyl-PTA iodide (CP16) and octadecyl-PTA iodide (CP18). The obtained CP-SLN are characterized by a positive charge on the surface and reproducible dimensions around 220 nm. These nanosystems are able to efficiently bind nucleic acid molecules and to protect DNA from the activity of serum nucleases up to 120 min. Lastly, in vitro experiments demonstrated that CP-SLN exhibit a quite pronounced antiproliferative effect on cultured human K562 erythroleukemic cells and a limited effect as transfecting adjuvant. These data, and particularly the ability of CP-SLN to protect DNA from degradation, encourages further studies aimed at proposing these nanosystems as a potential approach to deliver nucleic acid to cells in living organisms.

Synthesis, characterization of strontium-bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate.

The strontium salts Sr(cholate)2, (Compound 1), Sr(dehydrocholate)2, (Compound 2) and Sr3(3-dehydrocholanoyliden-L-tartrate)2, (Compound 3) have been prepared and characterized. The potential anti-osteoporotic activity of these compounds was tested on human primary osteoblasts (hOBs) and human primary osteoclasts (hOCs) in comparison with the bioactivity of strontium ranelate, previously registered as drug in the treatment of post-menopausal osteoporosis. Our results led to the hypothesis that the tested compounds, particularly Compound 2, may have requirements for modulating skeletal tissue regeneration or at least down regulating the loss of bone mass. In fact, all tested compounds have been shown to induce maturation in human primary osteoblasts (hOBs) and apoptosis of human primary osteoclasts (hOCs) at the same time.

Effects on erythroid differentiation of platinum(II) complexes of synthetic bile acid derivatives.

In this study, we compared some bile acid derivatives and their platinum(II) complexes with respect to their ability to induce erythroid differentiation of human leukemic K562 cells. The complexes analyzed were cis-[(3-dehydrocholanoyliden-L-tartrate)-diammineplatinum(II)] (compound 1) and cis-[di(dehydrocholanoate)-bis(triphenylphosphine)-platinum(II)] (compound 3), together with their free ligands, respectively, 3-dehydrocholanoyliden-L-tartaric acid (compound 2) and dehydrocholanoic acid (4), and their parent compounds, respectively, cisplatin and cis-[dichloride-bis(triphenylphosphine)-platinum(II)] (5). We found that compound 1 stimulates erythroid differentiation of K562 cells and an increase of fetal hemoglobin (HbF) production in erythroid precursor cells isolated from peripheral blood of human subjects. This increase is similar to that obtained by hydroxyurea, a potent inducer of HbF production both in vitro and in vivo. Another important conclusion of this study is related to the evaluation of the effects of compound 1 on production of gamma-globin mRNA in human erythroid precursors grown in the two-stage liquid culture system. We demonstrated that compound 1 induces preferential accumulation of gamma-globin mRNA. The results presented in this manuscript could have practical impact, since it is well known that an increase in HbF production could ameliorate the clinical status of patients with beta-thalassemia and sickle cell anemia.